This invention relates to the inhibition of endogenous prostaglandin synthesis, and provides a method for treating or alleviating pathological conditions associated with excessive or unbalanced synthesis of endogenous prostaglandins (PG). In particular, the invention relates to the therapeutic treatment of the bronchoconstriction of asthma and of the inflammation of rheumatoid arthritis.
Although prostaglandins are a natural ingredient of body tissues and fluids, they can elicit or intensify a variety of untowards effects, including vomiting, diarrhoea, cough, inflammation and pain. Research has indicated, for example, that PGs produce inflammation and pain and also potentiate the inflammatory effects of other mediators. [See Nature New Biol., 236, 141-142 and 240, 200-203 (1972) and Nature, 246, 217-219, (1973)].
PGE.sub.2, (and to a lesser extent, PGF.sub.2.alpha.), has been demonstrated to be present in exudates from inflamed tissues and has been shown to be produced by untoward stimulation. [See J. Pharm. Pharmac. 21, 216-128 (1969); Pharm. Res. Commun. 3, 13-19 (1971); and Prostaglandin Synthetase Inhibitors, 121-133 Raven, New York (1974)]. Since, under normal conditions, the tissue concentration of PGs is low, the release of PG at sites of inflammation is theorized to be due to biosynthesis of the PGs.
Excessive or unbalanced synthesis of prostaglandins can therefore be harmful. It occurs, for example, in rheumatoid arthritis and other forms of inflammation and inflammatory pain, in asthma, in endotoxin shock, and in certain pathological conditions, such as the diarrhoea frequently a ssociated with the presence of carcinoid tumors.
Prostaglandins are synthesized from unsaturated C-20 fatty acids, e.g., arachidonic acid, by an enzyme complex, prostaglandin synthetase, in the presence of a suitable cofactor. [See Biochim. Biophys. Acta, 90, 204 and 207 (1964)]. Sheep and bovine seminal vesicles (BSV) have been found to possess high activity for synthesizing prostaglandins from arachidonic acid; because of their greater availability, the majority of biosynthetic studies involving conversion of arachidonic acid into prostaglandins have been conducted using BSV.
Because PG synthesis occurs by the PG synthetase-catalyzed oxidative cyclization of arachidonic acid, measurement of inhibition of this synthesis can be accomplished by reacting a substance to be tested for inhibitory properties with arachidonic acid in the presence of PG synthetase. The amount of PG synthesized from the arachidonic acid in the presence of the test substance can be measured against the amount of PG synthesized in the absence of the test substance.
We have found that certain extracts or fractions of mammalian blood plasma have the property of inhibiting the in vitro synthesis of prostaglandins. These extracts can, therefore, be used to reduce or inhibit the activity of endogenous prostaglandin synthetase syand thereby treat or alleviate pathological conditions of the kinds already mentioned. The extracts which inhibit synthesis of prostaglandins are Cohn fraction IV, Cohn subfraction IV.sub.1, Cohn subfraction IV.sub.4 and the haptoglobins.